The compound of the structure
or its HCl salt.(hereinafter the above DPP4-inhibitor or saxagliptin) is an orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, which is a therapeutic agent for treatment of Type-2 diabetes mellitus which is disclosed in U.S. Pat. No. 6,395,767.
After a meal intake, insulinotropic hormone GLP-1 is released which in turn induces insulin release from the pancreas. Some of the GLP-1 is inactivated by the DPP4 present in plasma and intestinal capillary endothelium. Therefore, if the DPP4 is inhibited, more GLP-1 will be available to activate insulin release from the pancreas. The advantage of this mechanism of insulin release is that insulin is secreted only in response to a meal. Therefore, problems of hypoglycemia associated with other diabetes drugs will be less likely with a DPP4 inhibitor.
The above DPP4 inhibitor is a labile compound which is prone to an intra-molecular cyclization as shown below.

The resultant degradant, cyclic amidine (mainly cis-cyclic amidine (CA)), is not therapeutically active and therefore, its formation is not desirable. This cyclization reaction can occur both in solid state and solution state. The rate of intra-molecular cyclization is accelerated when formulations are subject to commonly used processing activities such as wet granulation, roller compaction, or tabletting. In addition, most commonly used excipients, when mixed with this compound, can accelerate the rate of cyclization. Moreover, the level of cis-cyclic amidine increases when the drug to excipient ratio increases posing more challenges for low strength dosage forms. Given these properties of the molecule, manufacture of a conventional tablet dosage form for the DPP4-inhibitor, which is a preferred dosage form, is not a viable option.
Currently, capsule formulations containing a dry mix of the DPP4-inhibitor and commonly used excipients are manufactured at a small scale and used for clinical studies. The scale up of capsule formulations containing the DPP4-inhibitor will also be problematic since it will involve milling to control the particle size of the DPP4-inhibitor so that capsules of lower strengths are manufactured without content uniformity problems.
Additionally, most of the therapeutic agents as a single entity or as a combination product for diabetes treatments are available in a tablet dosage form. Since a tablet dosage form using traditional manufacturing process is not feasible for the DPP4-inhibitor, its manufacturing with other therapeutic agents, as a combination tablet will be even more problematic.
Thus, it is seen that there is clearly a need for stable pharmaceutical formulations containing medicaments which are subject to intra-molecular cyclization which results in formation of degradants such as cyclic amidines which are not therapeutically active.
U.S. Pat. No. 6,395,767 to Robl et al. (hereinafter Robl et al.) discloses cyclopropyl-fused pyrrolidine-based dipeptidyl peptidase IV inhibitors (DPP4 inhibitors) which include compounds having the structure
or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt can be the hydrochloride salt or the trifluoroacetic acid salt.
Robl et al. discloses that the DPP4 inhibitors including those set out above may be formulated as tablets, capsules, granules or powders.